Endostatin, an Angiogenesis Inhibitor, Ameliorates Bleomycin-induced Pulmonary Fibrosis in Rats

Overview

Journal Respir Res

Specialty Pulmonary Medicine

Date 2013 May 22

PMID 23688086

Citations 29

Authors

Yun-Yan Wan

Guang-Yan Tian

Hai-Sheng Guo

Yan-Meng Kang

Zhou-Hong Yao

Xi-Li Li

Qing-Hua Liu

Dian-Jie Lin

Affiliations

Soon will be listed here.

Abstract

Background: Recent evidence has demonstrated the role of angiogenesis in the pathogenesis of pulmonary fibrosis. Endostatin, a proteolytic fragment of collagen XVIII, is a potent inhibitor of angiogenesis. The aim of our study was to assess whether endostatin has beneficial effects on bleomycin (BLM)-induced pulmonary fibrosis in rats.

Methods: The rats were randomly divided into five experimental groups: (A) saline only, (B) BLM only, (C) BLM plus early endostatin treatment, (D) BLM plus late endostatin treatment, and (F) BLM plus whole-course endostatin treatment. We investigated the microvascular density (MVD), inflammatory response and alveolar epithelial cell apoptosis in rat lungs in each group at different phases of disease development.

Results: Early endostatin administration attenuated fibrotic changes in BLM-induced pulmonary fibrosis in rats. Endostatin treatment decreased MVD by inhibiting the expression of VEGF/VEGFR-2 (Flk-1) and the activation of extracellular signal-regulated protein kinase 1/2 (ERK1/2). Endostatin treatment also decreased the number of inflammatory cells infiltrating the bronchoalveolar lavage fluid during the early inflammatory phase of BLM-induced pulmonary fibrosis. In addition, the levels of tumour necrosis factor-α (TNF-α) and transforming growth factor β1 (TGF-β1) were reduced by endostatin treatment. Furthermore, endostatin decreased alveolar type II cell apoptosis and had an epithelium-protective effect. These might be the mechanism underlying the preventive effect of endostatin on pulmonary fibrosis.

Conclusions: Our findings suggest that endostatin treatment inhibits the increased MVD, inflammation and alveolar epithelial cell apoptosis, consequently ameliorating BLM-induced pulmonary fibrosis in rats.

Citing Articles

Prolyl oligopeptidase inhibition ameliorates experimental pulmonary fibrosis both in vivo and in vitro.

Cucinotta L, Mannino D, Casili G, Repici A, Crupi L, Paterniti I Respir Res. 2023; 24(1):211.

PMID: 37626373 PMC: 10463606. DOI: 10.1186/s12931-023-02519-x.

The Preventive Effect of Endostar on Radiation-induced Pulmonary Fibrosis.

Ying H, Zhou C, Hang Q, Fang M Curr Mol Med. 2023; 24(5):610-619.

PMID: 37038709 DOI: 10.2174/1566524023666230406134640.

Ameliorating Fibrosis in Murine and Human Tissues with END55, an Endostatin-Derived Fusion Protein Made in Plants.

Mlakar L, Garrett S, Watanabe T, Sanderson M, Nishimoto T, Heywood J Biomedicines. 2022; 10(11).

PMID: 36359382 PMC: 9687961. DOI: 10.3390/biomedicines10112861.

The mapping of mRNA alterations elucidates the etiology of radiation-induced pulmonary fibrosis.

Yuan M, Zhao M, Sun X, Hui Z Front Genet. 2022; 13:999127.

PMID: 36353104 PMC: 9638132. DOI: 10.3389/fgene.2022.999127.

The effect of endostatin on angiogenesis and osteogenesis of steroid-induced osteonecrosis of the femoral head in a rabbit model.

Zhao Y, Li D, Duan D, Song Q Acta Orthop Traumatol Turc. 2022; 56(3):178-186.

PMID: 35703505 PMC: 9612648. DOI: 10.5152/j.aott.2022.21248.

References

OReilly M, Boehm T, Shing Y, Fukai N, Vasios G, Lane W . Endostatin: an endogenous inhibitor of angiogenesis and tumor growth. Cell. 1997; 88(2):277-85. DOI: 10.1016/s0092-8674(00)81848-6. View

Lee S, Jang A, Kim Y, Cha J, Kim T, Jung S . Modulation of cytokine and nitric oxide by mesenchymal stem cell transfer in lung injury/fibrosis. Respir Res. 2010; 11:16. PMC: 2827393. DOI: 10.1186/1465-9921-11-16. View

Galuppo M, Esposito E, Mazzon E, Di Paola R, Paterniti I, Impellizzeri D . MEK inhibition suppresses the development of lung fibrosis in the bleomycin model. Naunyn Schmiedebergs Arch Pharmacol. 2011; 384(1):21-37. DOI: 10.1007/s00210-011-0637-7. View

Keane M, Belperio J, Arenberg D, Burdick M, Xu Z, Xue Y . IFN-gamma-inducible protein-10 attenuates bleomycin-induced pulmonary fibrosis via inhibition of angiogenesis. J Immunol. 1999; 163(10):5686-92. View

Wang X, Zhu H, Yang X, Bi Y, Cui S . Vasohibin attenuates bleomycin induced pulmonary fibrosis via inhibition of angiogenesis in mice. Pathology. 2010; 42(5):457-62. DOI: 10.3109/00313025.2010.493864. View

Sumi M, Satoh H, Kagohashi K, Ishikawa H, Sekizawa K . Increased serum levels of endostatin in patients with idiopathic pulmonary fibrosis. J Clin Lab Anal. 2005; 19(4):146-9. PMC: 6807939. DOI: 10.1002/jcla.20069. View

Hamada N, Kuwano K, Yamada M, Hagimoto N, Hiasa K, Egashira K . Anti-vascular endothelial growth factor gene therapy attenuates lung injury and fibrosis in mice. J Immunol. 2005; 175(2):1224-31. DOI: 10.4049/jimmunol.175.2.1224. View

Usuki J, Fukuda Y . Evolution of three patterns of intra-alveolar fibrosis produced by bleomycin in rats. Pathol Int. 1995; 45(8):552-64. DOI: 10.1111/j.1440-1827.1995.tb03503.x. View

Drakopanagiotakis F, Xifteri A, Polychronopoulos V, Bouros D . Apoptosis in lung injury and fibrosis. Eur Respir J. 2008; 32(6):1631-8. DOI: 10.1183/09031936.00176807. View

10.

Ziche M, Morbidelli L, Choudhuri R, Zhang H, Donnini S, Granger H . Nitric oxide synthase lies downstream from vascular endothelial growth factor-induced but not basic fibroblast growth factor-induced angiogenesis. J Clin Invest. 1997; 99(11):2625-34. PMC: 508108. DOI: 10.1172/JCI119451. View

11.

Ashcroft T, Simpson J, Timbrell V . Simple method of estimating severity of pulmonary fibrosis on a numerical scale. J Clin Pathol. 1988; 41(4):467-70. PMC: 1141479. DOI: 10.1136/jcp.41.4.467. View

12.

Tolstanova G, Deng X, Khomenko T, Garg P, Paunovic B, Chen L . Role of anti-angiogenic factor endostatin in the pathogenesis of experimental ulcerative colitis. Life Sci. 2010; 88(1-2):74-81. PMC: 9552542. DOI: 10.1016/j.lfs.2010.10.026. View

13.

Panos R, Mortenson R, Niccoli S, King Jr T . Clinical deterioration in patients with idiopathic pulmonary fibrosis: causes and assessment. Am J Med. 1990; 88(4):396-404. DOI: 10.1016/0002-9343(90)90495-y. View

14.

Farkas L, Gauldie J, Voelkel N, Kolb M . Pulmonary hypertension and idiopathic pulmonary fibrosis: a tale of angiogenesis, apoptosis, and growth factors. Am J Respir Cell Mol Biol. 2010; 45(1):1-15. DOI: 10.1165/rcmb.2010-0365TR. View

15.

Weidner N . Intratumor microvessel density as a prognostic factor in cancer. Am J Pathol. 1995; 147(1):9-19. PMC: 1869874. View

16.

Shimizu M, Saitoh Y, Itoh H . Immunohistochemical staining of Ha-ras oncogene product in normal, benign, and malignant human pancreatic tissues. Hum Pathol. 1990; 21(6):607-12. DOI: 10.1016/s0046-8177(96)90006-4. View

17.

TURNER-WARWICK M . PRECAPILLARY SYSTEMIC-PULMONARY ANASTOMOSES. Thorax. 1963; 18:225-37. PMC: 1018768. DOI: 10.1136/thx.18.3.225. View

18.

. American Thoracic Society. Idiopathic pulmonary fibrosis: diagnosis and treatment. International consensus statement. American Thoracic Society (ATS), and the European Respiratory Society (ERS). Am J Respir Crit Care Med. 2000; 161(2 Pt 1):646-64. DOI: 10.1164/ajrccm.161.2.ats3-00. View

19.

Yoshida K, Kuwano K, Hagimoto N, Watanabe K, Matsuba T, Fujita M . MAP kinase activation and apoptosis in lung tissues from patients with idiopathic pulmonary fibrosis. J Pathol. 2002; 198(3):388-96. DOI: 10.1002/path.1208. View

20.

Ota K . [Diagnosis and treatment of idiopathic pulmonary fibrosis]. Nihon Naika Gakkai Zasshi. 2007; 96(3):557-61. DOI: 10.2169/naika.96.557. View